Food increases the bioavailability of propafenone.

Axelson, James E.; Chan, Grace; Kirsten, Edward B.; Mason, William D.; Lanman, Robert C.; Kerr, C. R.

doi:10.1111/j.1365-2125.1987.tb03109.x

Cited by 39 publications

(11 citation statements)

References 23 publications

(35 reference statements)

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“…h-ml ~ in the 7 subjects who participated both in the current and the previous study [ That the phenomenon was transient is also apparent from the fact that food did not enhance the bioavailability of propranolol given in a slow-release formulation [4,9]. A recent study on a propranolol-like compound, propafenone, showed that the extent of the food effect might depend upon the extent of oral clearance [15]. The current study showed a similar dependence for propranolol itself.…”

Section: Discussionsupporting

confidence: 69%

“…As the current and previous studies [2,3,6] have shown little or no effect of a carbohydrate meal on propranolol bioavailability, the effect of a protein-rich meal may be caused by a transient increase in splanchnichepatic blood flow. However, the food-induced increase in splanchnic-hepatic blood flow is hardly sufficient to explain the entire food effect on propranolol or propafenone bioavailability, which can exceed 300 and 700%, respectively, in individuals with a particularly high clearance [4,11,15]. Furthermore, a posture-induced increase in splanchnic-hepatic blood flow, equal to that caused by food intake, does not enhance propranolol bioavailability [13].…”

Section: Discussionmentioning

confidence: 89%

“…A possible reason for the variation has emerged from a study on a related drug, propafenone, indicating that the food effect increases with the oral metabolic clearance [15]. The current study is an…”

mentioning

confidence: 95%

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Mechanisms and variations in the food effect on propranolol bioavailability

Liedholm

Wåhlin-Boll

Melander

1990

Eur J Clin Pharmacol

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Mechanisms and variations in the food-induced increase in the bioavailability of propranolol were assessed by single-dose (80 mg) studies in healthy volunteers who took the drug on an empty stomach, immediately after a protein-rich breakfast, and together with a carbohydrate-rich, protein-poor breakfast. Concomitant intake of the protein-rich, but not the carbohydrate-rich, protein-poor breakfast, increased the bioavailability of propranolol in most, but not all, subjects. The food (protein) effect displayed much inter-individual variation, from a decrease to a 250% increase, which could be explained, at least in part, by a correlation between the oral clearance of propranolol and the food-induced increase in its bioavailability. The food effect was not associated with decreased total availability, but with delayed appearance, of the oxidative metabolites 4-OHP, NLA and PG. Hence the food (protein) effect does not seem to be caused by enzyme inhibition, but rather it is due to reduced hepatic extraction of propranolol, probably consequent to an increase hepatic entry rate. When taken together with the protein-rich breakfast, propranolol usually appeared in systemic blood at least as early as when taken on an empty stomach, implying that gastric absorption of propranolol may be possible in the presence of protein-rich food. Within the individual the food effect was reproducible, but its magnitude showed an intraindividual variation that may reflect its dependence upon the rates of gastrointestinal absorption and splanchnic-hepatic blood flow, and hence upon the rate of hepatic drug entry.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 89%

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Mechanisms and variations in the food effect on propranolol bioavailability

Liedholm

Wåhlin-Boll

Melander

1990

Eur J Clin Pharmacol

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“…Also, food has been shown to increase the bioavailability of propafenone in EM but not in PM of the drug (Axelson et al, 1987). This suggests that some element(s) in the meal tested competed with substrates metabolized by the same isozymes as those responsible for the oxidation of debrisoquine.…”

Section: Discussionmentioning

confidence: 99%

Genetically‐determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

Funck‐Brentano

Kroemer

Pavlou

et al. 1989

Brit J Clinical Pharma

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1 Quinidine is a potent inhibitor of the genetically-determined debrisoquine 4-hydroxylation. Oxidation reactions of several other drugs, including the 5-hydroxylation of the new antiarrhythmic drug propafenone, depend on the isozyme responsible for debrisoquine 4-hydroxylation.2 The effect of quinidine on the debrisoquine phenotype-dependent 5-hydroxylation and the pharmacological activity of propafenone was studied in seven 'extensive' metabolizers and two 'poor' metabolizers of the drug receiving propafenone for the treatment of ventricular arrhythmias. 3 In patients with the extensive metabolizer phenotype, quinidine increased mean steady-state plasma propafenone concentrations more than two fold, from 408 ± 351 (mean ± s.d.) to 1096 ± 644 ng ml-' (P < 0.001), decreased 5-hydroxypropafenone concentrations from 242 ± 196 to 125 ± 97 ng ml-' (P < 0.02) and reduced propafenone oral clearance by 58 ± 23%. 4 Despite these changes in plasma concentrations, electrocardiographic intervals and arrhythmia frequency were unaltered by quinidine coadministration, indicating that 5-hydroxypropafenone contributes to the pharmacologic effects of propafenone therapy in extensive metabolizers.5 In contrast, plasma concentrations of propafenone and 5-hydroxypropafenone remained unchanged in the two patients with the poor metabolizer phenotype. 6 Biotransformation of substrates for the debrisoquine pathway can be markedly perturbed by even low doses of quinidine; interindividual variability in drug interactions may have a genetic component.

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“…This pathway is polymorphically expressed in humans and is under genetic control, co-segregating with a well-described debrisoquine oxidation polymorphism, 3 such that poor metabolizers can be distinguished from extensive metabolizers. 4 An additional route of propafenone metabolism is N-demethylation to N-despropylpropafenone, which is primarily mediated via CYP3A4 and CYP1A2. 5 Five hydroxy-propafenone has been shown to exert pharmacologic activity comparable to that of the parent drug.…”

Section: Introductionmentioning

confidence: 99%

A Rapid HPLC Assay for the Simultaneous Determination of Propafenone and Its Major Metabolites in Human Serum

Afshar

Rouini

2004

ANAL. SCI.

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Propafenone is a potent antiarrhythmic drug, which is widely used in the treatment of ventricular and supraventricular arrhythmias. 1 It blocks the fast inward sodium current in all cardiac and other excitable tissues, like the central nervous system. Propafenone also has some β-blocking action, much less than that of propranolol, and a weak calcium-channelblocking effect. 2 Propafenone undergoes extensive first-pass metabolism by the liver to form several metabolites. The main metabolic pathway of propafenone is ring hydroxylation to 5-OH-propafenone, being primarily mediated by CYP2D6. This pathway is polymorphically expressed in humans and is under genetic control, co-segregating with a well-described debrisoquine oxidation polymorphism, 3 such that poor metabolizers can be distinguished from extensive metabolizers. 4 An additional route of propafenone metabolism is N-demethylation to N-despropylpropafenone, which is primarily mediated via CYP3A4 and CYP1A2.5 Five hydroxy-propafenone has been shown to exert pharmacologic activity comparable to that of the parent drug. 6Although N-despropylpropafenone exerted antiarrhythmic activity in animal experiments, 7 relatively little is known about its pharmacokinetics and pharmacodynamics in humans. The metabolic pathway of propafenone is illustrated in Fig. 1.The specific metabolism of propafenone, its potential drug-drug interactions and its widespread use have stimulated efforts to develop routine assays for this drug and its metabolites in human serum. Several chromatographic methods have been reported for the determination of propafenone and 5-OH-propafenone in biological matrices, including highperformance liquid chromatography (HPLC) [8][9][10][11][12][13][14][15]18 and gas chromatography. 16,17 For HPLC assays, different modes of detection have been employed, including UV 8-15 and fluorescence with precolumn derivatization. 18Most of these methods have only been validated for propafenone, itself, or propafenone and 5-OH-propafenone. The resolution of N-despropylpropafenone, which is probably co-eluted under reported procedures, was rarely investigated.Among the methods described so far, only a few allow for the determination of the serum or plasma concentrations of propafenone and its main metabolites in a single run. A rapid and specific HPLC method has been developed and validated for the simultaneous determination of propafenone, an antiarrhythmic agent, and its major metabolites in human serum. The sample preparation was a simple deproteinization with a mixture of ZnSO4 and methanol, yielding almost 100% recoveries of three compounds. Separation was developed on a reverse-phase tracer excel C18 column (25 × 0.46 cm i.d., 5 µm), using an acetonitrilephosphate buffer gradient at a flow rate of 1.7 ml min -1 , and UV detection of 210 nm. The calibration curves were linear (r 2 > 0.999) in the concentration range of 10 -750 ng ml -1 . The lower limit of quantification was 10 ng ml -1 for all of the compounds studied. The within and between day precisions in th...

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Food increases the bioavailability of propafenone.

Cited by 39 publications

References 23 publications

Mechanisms and variations in the food effect on propranolol bioavailability

Mechanisms and variations in the food effect on propranolol bioavailability

Genetically‐determined interaction between propafenone and low dose quinidine: role of active metabolites in modulating net drug effect.

A Rapid HPLC Assay for the Simultaneous Determination of Propafenone and Its Major Metabolites in Human Serum

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